The ubiquitously expressed highly polymorphic classical class 1 MHC antigens participate in elimination of virally infected, malignantly transformed and allogeneic cells. In contrast very little is currently known about oligomorphic nonclassical transplantation antigens. These beta-2m-associated molecules resemble structurally the classical class 1 proteins but differ in patterns and levels of expression and the type of ligands that they associate with. The tissue-restricted class molecule that we study is the murine Qa-2 antigen encoded by the Q9 gene of C57BL/10 mice. Qa-2 can bind a diverse array of peptides similar to class la ligands, consistent with the assumption that it may be involved in antigen presentation to T-cells and/or regulation of natural immunity by NK cells. Identification of Qa-2 in immunologically-privileged tissue and its restricted tissue distribution suggest that this molecule may have novel or altered functions compared to the class 1 antigens. This hypothesis will be tested in the proposed studies. The specific aims are: 1) to construct transgenic mice expressing single-chain Qa-2 (SCQ-2) as their only biochemically abundant class 1 molecule in beta2m-deficient C57BL/6 mice; 2) to characterize in detail tissue, cell and tumor destruction of wild type Qa-2 transcripts and proteins and to compare it to tissue distribution of SCQa-2 molecules in the transgenic mice; 3) to examine development of alpha/beta T-cells and T-cell responses controlled by Qa-2 antigens in transgenic mice; 4) to test a hypothesis that Qa-2 functions as an inhibitory or a positive recognition target for NK receptors. The results of the studies described in this application will permit to assess biological functions of the model tissue specific transplantation antigen Qa-2. This information may be helpful in the development of unrestricted peptide vaccines against pathogens and tumors and in future design of more efficient strategies for transplantation and suppression of autoimmune reactions.